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      Polyploidy of semi-cloned embryos generated from parthenogenetic haploid embryonic stem cells

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          Abstract

          In mammals, the fusion of two gametes, an oocyte and a spermatozoon, during fertilization forms a totipotent zygote. There has been no reported case of adult mammal development by natural parthenogenesis, in which embryos develop from unfertilized oocytes. The genome and epigenetic information of haploid gametes are crucial for mammalian development. Haploid embryonic stem cells (haESCs) can be established from uniparental blastocysts and possess only one set of chromosomes. Previous studies have shown that sperm or oocyte genome can be replaced by haESCs with or without manipulation of genomic imprinting for generation of mice. Recently, these remarkable semi-cloning methods have been applied for screening of key factors of mouse embryonic development. While haESCs have been applied as substitutes of gametic genomes, the fundamental mechanism how haESCs contribute to the genome of totipotent embryos is unclear. Here, we show the generation of fertile semi-cloned mice by injection of parthenogenetic haESCs (phaESCs) into oocytes after deletion of two differentially methylated regions (DMRs), the IG-DMR and H19-DMR. For characterizing the genome of semi-cloned embryos further, we establish ESC lines from semi-cloned blastocysts. We report that polyploid karyotypes are observed in semi-cloned ESCs (scESCs). Our results confirm that mitotically arrested phaESCs yield semi-cloned embryos and mice when the IG-DMR and H19-DMR are deleted. In addition, we highlight the occurrence of polyploidy that needs to be considered for further improving the development of semi-cloned embryos derived by haESC injection.

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          Most cited references 31

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          From polyploidy to aneuploidy, genome instability and cancer.

          Polyploidy is a frequent phenomenon in the eukaryotic world, but the biological properties of polyploid cells are not well understood. During evolution, polyploidy is thought to be an important mechanism that contributes to speciation. Polyploid, usually non-dividing, cells are formed during development in otherwise diploid organisms. A growing amount of evidence indicates that polyploid cells also arise during a variety of pathological conditions. Genetic instability in these cells might provide a route to aneuploidy and thereby contribute to the development of cancer.
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            Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12.

            Genomic imprinting causes parental origin-specific gene expression. Cis-acting regulatory elements that control imprinting are not fully understood but involve regions that become differentially methylated on the two parental chromosomes during male and female gametogenesis. Understanding properties of maternally and paternally inherited imprints provides insight into the mechanisms and evolution of genomic imprinting. Previously we identified an intergenic germline-derived differentially methylated region (IG-DMR) that is a candidate control element for an imprinted domain on distal mouse chromosome 12 (ref. 5). The 1-Mb cluster contains the paternally expressed protein-coding genes Dlk1 (refs. 6,7) and Dio3 (ref. 8,9) and several maternally expressed non-coding RNAs, including Gtl2 (refs. 6,7,10) and C/D snoRNAs. A retrotransposon-like gene (Rtl1) is expressed from the paternal chromosome and has an antisense transcript expressed from the maternal chromosome containing two microRNAs with full complementarity to Rtl1 (ref. 12). Here we show that deletion of the IG-DMR from the maternally inherited chromosome causes bidirectional loss of imprinting of all genes in the cluster. When the deletion is transmitted from the father, imprinting is unaltered. These results prove that the IG-DMR is a control element for all imprinted genes on the maternal chromosome only and indicate that the two parental chromosomes control allele-specific gene expression differently.
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              Disruption of imprinting caused by deletion of the H19 gene region in mice.

              The imprinted H19 gene, which encodes an untranslated RNA, lies at the end of a cluster of imprinted genes in the mouse. Imprinting of the insulin-2 and insulin-like growth factor 2 genes, which lie about 100 kilobases upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers are 27% heavier than those inheriting it from their fathers. Paternal inheritance of the disruption has no effect, which presumably reflects the normally silent state of the paternal gene. The somatic overgrowth of heterozygotes for the maternal deletion is attributed to a gain of function of insulin-like growth factor 2, rather than a loss of function of H19.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 September 2020
                2020
                : 15
                : 9
                Affiliations
                Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland
                Instituto Aragones de Ciencias de la Salud, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-20-12064
                10.1371/journal.pone.0233072
                7482839
                © 2020 Aizawa et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 2, Pages: 14
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 31003A_152814/1
                Award Recipient :
                AW, grant 31003A_152814/1 from the Swiss National Science Foundation, WEB page: www.snf.ch The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Embryos
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Oocytes
                Biology and Life Sciences
                Genetics
                Genomics
                Animal Genomics
                Mammalian Genomics
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Blastocysts
                Biology and Life Sciences
                Genetics
                Departures from Diploidy
                Polyploidy
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                Sperm
                Biology and life sciences
                Cell biology
                Chromosome biology
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                DNA modification
                DNA methylation
                Biology and Life Sciences
                Genetics
                Departures from Diploidy
                Polyploidy
                Tetraploidy
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

                Uncategorized

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